Dataset Information

Emergence and Within-Host Genetic Evolution of Methicillin-Resistant Staphylococcus aureus Resistant to Linezolid in a Cystic Fibrosis Patient.

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) infection has increased in recent years among cystic fibrosis (CF) patients. Linezolid (LZD) is one of the antistaphylococcal antibiotics widely used in this context. Although LZD resistance is rare, it has been described as often associated with long-term treatments. Thirteen MRSA strains isolated over 5?years from one CF patient were studied for LZD resistance emergence and subjected to whole-genome sequencing (WGS). Resistance emerged after three 15-day LZD therapeutic regimens over 4?months. It was associated with the mutation of G to T at position 2576 (G2576T) in all 5 rrl copies, along with a very high MIC (>256?mg/liter) and a strong increase in the generation time. Resistant strains isolated during the ensuing LZD therapeutic regimens and until 13?months after LZD stopped harbored only 3 or 4 mutated rrl copies, associated with lower MICs (8 to 32?mg/liter) and low to moderate generation time increases. Despite these differences, whole-genome sequencing allowed us to determine that all isolates, including the susceptible one isolated before LZD treatment, belonged to the same lineage. In conclusion, LZD resistance can emerge rapidly in CF patients and persist without linezolid selective pressure in colonizing MRSA strains belonging to the same lineage.

SUBMITTER: Rouard C

PROVIDER: S-EPMC6256785 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Emergence and Within-Host Genetic Evolution of Methicillin-Resistant <i>Staphylococcus aureus</i> Resistant to Linezolid in a Cystic Fibrosis Patient.

Rouard Caroline C Garnier Fabien F Leraut Jeremy J Lepainteur Margaux M Rahajamananav Lalaina L Languepin Jeanne J Ploy Marie-Cécile MC Bourgeois-Nicolaos Nadège N Doucet-Populaire Florence F

Antimicrobial agents and chemotherapy 20181126 12

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection has increased in recent years among cystic fibrosis (CF) patients. Linezolid (LZD) is one of the antistaphylococcal antibiotics widely used in this context. Although LZD resistance is rare, it has been described as often associated with long-term treatments. Thirteen MRSA strains isolated over 5 years from one CF patient were studied for LZD resistance emergence and subjected to whole-genome sequencing (WGS). Resistance emerged ...[more]

PMID: 30275089

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Project description:Linezolid is an antibiotic used to treat serious Staphylococcus aureus infections. Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of linezolid for a cohort of patients with cystic fibrosis (CF). The goals of this study were to determine the incidence of linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) in CF and identify molecular mechanisms for linezolid resistance. We identified patients who cultured S. aureus resistant to linezolid with minimum inhibitory concentration (MIC) >4 at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid-resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance. Between 2008 and 2018, 111 patients received linezolid, and 4 of these patients cultured linezolid-resistant S. aureus. We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid-resistant S. aureus with a G2576T mutation in 23S rRNA. One of these subjects additionally had a mutS- mutL- hypermutating S. aureus that produced five resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear. We conclude that linezolid resistant S. aureus can occur through multiple genetic mechanisms in patients with repeated exposure to this antibiotic. IMPORTANCE Patients with cystic fibrosis have persistent lung infections with Staphylococcus aureus that require extensive antibiotic treatments. Linezolid, an antibiotic given by oral or intravenous route, is prescribed repeatedly for patients whose lung disease has progressed. After treatment with linezolid, S. aureus strains can evolve antibiotic resistance through multiple genetic mechanisms. In addition to a common mutation in the 23S ribosomal RNA known to confer linezolid resistance, S. aureus strains can evolve novel resistance based on a combination of mutations affecting the bacterial ribosome. This combination of mutations was observed in a strain that exhibited hypermutation owing to the loss of the DNA repair genes mutS and mutL. In this cohort of patients with cystic fibrosis, linezolid resistance was transient, possibly due to the growth disadvantage of resistant strains. However, ongoing chronic exposure to linezolid may create optimal conditions for the future emergence of resistance to this critical antibiotic.

Dataset Information

Emergence and Within-Host Genetic Evolution of Methicillin-Resistant Staphylococcus aureus Resistant to Linezolid in a Cystic Fibrosis Patient.

Publications

Emergence and Within-Host Genetic Evolution of Methicillin-Resistant <i>Staphylococcus aureus</i> Resistant to Linezolid in a Cystic Fibrosis Patient.

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